4i11

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{{STRUCTURE_4i11| PDB=4i11 | SCENE= }}
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==Structure-based design of novel dihydroisoquinoline BACE-1 inhibitors that do not engage the catalytic aspartates.==
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===Structure-based design of novel dihydroisoquinoline BACE-1 inhibitors that do not engage the catalytic aspartates.===
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<StructureSection load='4i11' size='340' side='right' caption='[[4i11]], [[Resolution|resolution]] 1.89&Aring;' scene=''>
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{{ABSTRACT_PUBMED_23465612}}
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== Structural highlights ==
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<table><tr><td colspan='2'>[[4i11]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4I11 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4I11 FirstGlance]. <br>
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==Function==
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1CH:N-(3,3-DIMETHYL-3,4-DIHYDROISOQUINOLIN-1-YL)-L-PHENYLALANINE'>1CH</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4hzt|4hzt]], [[4i0z|4i0z]], [[4i10|4i10]]</td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BACE1, BACE, KIAA1149 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Memapsin_2 Memapsin 2], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.46 3.4.23.46] </span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4i11 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4i11 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4i11 RCSB], [http://www.ebi.ac.uk/pdbsum/4i11 PDBsum]</span></td></tr>
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</table>
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== Function ==
[[http://www.uniprot.org/uniprot/BACE1_HUMAN BACE1_HUMAN]] Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase.<ref>PMID:10677483</ref> <ref>PMID:20354142</ref>
[[http://www.uniprot.org/uniprot/BACE1_HUMAN BACE1_HUMAN]] Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase.<ref>PMID:10677483</ref> <ref>PMID:20354142</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The structure-activity relationship of a series of dihydroisoquinoline BACE-1 inhibitors is described. Application of structure-based design to screening hit 1 yielded sub-micromolar inhibitors. Replacement of the carboxylic acid of 1 was guided by X-ray crystallography, which allowed the replacement of a key water-mediated hydrogen bond. This work culminated in compounds such as 31, which possess good BACE-1 potency, excellent permeability and a low P-gp efflux ratio.
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Structure-based design of novel dihydroisoquinoline BACE-1 inhibitors that do not engage the catalytic aspartates.,Bowers S, Xu YZ, Yuan S, Probst GD, Hom RK, Chan W, Konradi AW, Sham HL, Zhu YL, Beroza P, Pan H, Brecht E, Yao N, Lougheed J, Tam D, Ren Z, Ruslim L, Bova MP, Artis DR Bioorg Med Chem Lett. 2013 Apr 1;23(7):2181-6. doi: 10.1016/j.bmcl.2013.01.103., Epub 2013 Feb 4. PMID:23465612<ref>PMID:23465612</ref>
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[4i11]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4I11 OCA].
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</div>
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==Reference==
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==See Also==
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<references group="xtra"/><references/>
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*[[Beta secretase|Beta secretase]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Memapsin 2]]
[[Category: Memapsin 2]]
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[[Category: Artis, D R.]]
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[[Category: Artis, D R]]
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[[Category: Beroza, P.]]
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[[Category: Beroza, P]]
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[[Category: Bova, M.]]
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[[Category: Bova, M]]
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[[Category: Bowers, B.]]
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[[Category: Bowers, B]]
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[[Category: Brecht, E.]]
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[[Category: Brecht, E]]
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[[Category: Chan, W.]]
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[[Category: Chan, W]]
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[[Category: Hom, R K.]]
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[[Category: Hom, R K]]
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[[Category: Konradi, A W.]]
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[[Category: Konradi, A W]]
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[[Category: Lougheed, J.]]
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[[Category: Lougheed, J]]
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[[Category: Pan, H.]]
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[[Category: Pan, H]]
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[[Category: Probst, G D.]]
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[[Category: Probst, G D]]
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[[Category: Sham, H L.]]
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[[Category: Sham, H L]]
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[[Category: Tam, D.]]
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[[Category: Tam, D]]
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[[Category: Xu, Y.]]
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[[Category: Xu, Y]]
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[[Category: Yao, N.]]
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[[Category: Yao, N]]
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[[Category: Yuan, S.]]
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[[Category: Yuan, S]]
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[[Category: Zhu, Y L.]]
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[[Category: Zhu, Y L]]
[[Category: Bace-1]]
[[Category: Bace-1]]
[[Category: Transferase-transferase inhibitor complex]]
[[Category: Transferase-transferase inhibitor complex]]

Revision as of 13:49, 25 December 2014

Structure-based design of novel dihydroisoquinoline BACE-1 inhibitors that do not engage the catalytic aspartates.

4i11, resolution 1.89Å

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